WO2020108478A1 - Composé de thiamine, son procédé de préparation et composition pharmaceutique associée - Google Patents

Composé de thiamine, son procédé de préparation et composition pharmaceutique associée Download PDF

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Publication number
WO2020108478A1
WO2020108478A1 PCT/CN2019/120942 CN2019120942W WO2020108478A1 WO 2020108478 A1 WO2020108478 A1 WO 2020108478A1 CN 2019120942 W CN2019120942 W CN 2019120942W WO 2020108478 A1 WO2020108478 A1 WO 2020108478A1
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group
thiamine
formula
methyl
mercapto
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PCT/CN2019/120942
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English (en)
Chinese (zh)
Inventor
钟春玖
张寰
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上海日馨生物科技有限公司
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Priority to JP2021531390A priority Critical patent/JP7307979B2/ja
Priority to US17/298,214 priority patent/US11591354B2/en
Priority to EP19888995.8A priority patent/EP3889160A4/fr
Publication of WO2020108478A1 publication Critical patent/WO2020108478A1/fr
Priority to JP2023039009A priority patent/JP2023085312A/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a thiamine compound, a preparation method and a pharmaceutical composition thereof.
  • AD Alzheimer's disease
  • a ⁇ ⁇ -amyloid
  • phenothiamine can reduce the deposition of ⁇ -amyloid (A ⁇ ) and Tau protein phosphate in the brain by inhibiting the activity of Glycogensynthasekinase-3 (GSK-3) Reduce the occurrence of pathological damage to Alzheimer’s disease. Therefore, the synthetic methods and crystalline forms of benfotiamine and its application in the treatment of Alzheimer's disease have been successively researched and reported. However, no relevant research reports on other phosphothiamine compounds have been found.
  • the specific embodiments of the present invention provide a novel thiamine compound, a preparation method, and a technical solution of the pharmaceutical composition:
  • a thiamine compound the structure of which is the following formula (1) or formula (2),
  • R 1 , R 2 , R 3 , R 4 , R 5 or R 6 are independently hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, ester group, carboxyl group, hydroxyl group , Mercapto, hydrocarbon mercapto, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted hydrocarbyloxy, acyl or amide.
  • the structure of the thiamine compound is as shown in formula (1), R 1 and R 2 are hydrogen atoms, and R 3 is benzyl or 1,5 difluorophenyl.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 or R 6 is independently a hydrogen atom or a C1-C18 chain hydrocarbon group.
  • R 1 or R 2 are independently a hydrogen atom, a methyl group or an ethyl group, and R 3 is a C1-C10 chain hydrocarbon group.
  • the structure of the thiamine compound is as shown in formula (1), wherein R 1 is a hydrogen atom, R 2 is a methyl group, and R 3 is a methyl or ethyl group.
  • the structure of the thiamine compound is represented by formula (1), wherein R 1 is a methyl group, R 2 is a methyl group, and R 3 is a vinyl group.
  • the structure of the thiamine compound is as shown in formula (2), R 5 is a hydrogen atom, and R 4 is n-propyl group.
  • the preparation method of the thiamine compound is obtained by reacting the thioamine phosphate represented by formula (1a) with the acid chloride represented by formula (1b) or (2b);
  • R 1 , R 2 , R 3 , R 4 , R 5 or R 6 are independently hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, ester group, carboxyl group, hydroxyl group , Mercapto, hydrocarbon mercapto, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted hydrocarbyloxy, acyl or amide.
  • the pharmaceutical composition comprises any of the thiamine compounds and their isomers or salts of thiamine compounds and their isomers.
  • the pharmaceutical composition is used to prepare drugs for preventing and treating neurodegenerative diseases.
  • the pharmaceutical composition is used to prepare drugs for preventing and treating Alzheimer's disease or aging.
  • the embodiments of the present invention provide a series of thiamine compounds of formula (1) or formula (2), which have an inhibitory effect on A ⁇ 40 and/or A ⁇ 42; further, the thiamine
  • the structure of the compound is as shown in formula (1), wherein R 1 is a hydrogen atom, R 2 is a methyl group, R 3 is a methyl group or an ethyl group, or the R 1 is a methyl group, R 2 is a methyl group, and R 3 is a vinyl or n-butyl, or the sulphonamide compounds of formula (2), the R4 and R 5 is a hydrogen atom, R 6 is n-propyl, having a more prominent inhibition of A ⁇ 40 and A ⁇ 42.
  • the thiamine compound according to the embodiment of the present invention has the following formula (1) or formula (2),
  • R 1 , R 2 , R 3 , R 4 , R 5 or R 6 are independently hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, ester group, carboxyl group, hydroxyl group , Mercapto, hydrocarbon mercapto, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted hydrocarbyloxy, acyl or amide.
  • the substituent includes a linear, branched or cyclic hydrocarbon group
  • the hydrocarbon group may be an alkane group, or an alkene group, alkyne group or aromatic hydrocarbon group.
  • the The hydrocarbon group is an alkane group, specifically, for example, methyl, ethyl, vinyl, propenyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, 1-ethylpropyl , 1-methylbutyl, cyclopentyl, hexyl, 1-methylpentyl, 1-ethylbutyl, cyclohexyl, 2-heptyl, heptyl, octyl, nonyl, decyl, undecyl Alkyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexyl, hexyl, 2-h
  • the substituted hydrocarbon group includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, hydrocarbyloxy substitution, amine substitution, carboxyl substitution, hydroxyl substitution, or mercapto substitution of the above hydrocarbon group And the like, specifically, for example, methoxyethyl, ethoxyethyl, butoxyethyl, trifluoromethyl, pentafluoroethyl, or the like.
  • the hydrocarbyloxy group includes a linear, branched or cyclic hydrocarbyloxy group, specifically, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy Group, tert-butoxy, isobutoxy, pentyloxy, 1-ethylpropoxy, 1-methylbutoxy, cyclopentyloxy, hexyloxy, 1-methylpentyloxy, 1 -Ethylbutoxy, cyclohexyloxy, 2-heptyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy Radical, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, ei
  • the substituted hydrocarbyloxy group includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, hydrocarbyloxy substitution, amine substitution, carboxyl substitution, hydroxyl group of the above hydrocarbyloxy group Substitution or mercapto substitution, etc., specifically, for example, methoxyethoxy, ethoxyethoxy, butoxyethoxy, trifluoromethoxy, or pentafluoroethoxy.
  • the hydrocarbon mercapto group includes a linear, branched or cyclic hydrocarbon mercapto group, specifically, for example, methyl mercapto group, ethyl mercapto group, n-propyl mercapto group, isopropyl mercapto group, n-butyl mercapto group, tert-butyl mercapto group, isobutyl Butylmercapto, pentylmercapto, 1-ethylpropylmercapto, 1-methylbutylmercapto, cyclopentylmercapto, hexylmercapto, 1-methylpentylmercapto, 1-ethylbutylmercapto, cyclohexylmercapto, 2-heptylmercapto , Heptyl mercapto, octyl mercapto, nonyl mercapto, decyl mercapto, undecyl
  • the substituted hydrocarbon mercapto group includes the halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, hydrocarbon mercapto substitution, amine substitution, carboxy substitution, hydroxyl substitution or mercapto group of the above hydrocarbon mercapto group
  • the substitution and the like are specifically exemplified by methoxyethylmercapto, ethoxyethylmercapto, butoxyethylmercapto, trifluoromethylmercapto, or pentafluoroethylmercapto.
  • the acyl group includes various hydrocarbyl acyl groups or various substituted hydrocarbyl acyl groups, and the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, amine substitution, carboxy substitution , Hydroxy substitution or mercapto substitution, etc., for example, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, t-butyryl, isobutyryl, valeryl, 1-ethylpropionyl, 1-methyl Butyryl, cyclopentanoyl, hexanoyl, 1-methylvaleryl, 1-ethylbutyryl, cyclohexanoyl, 2-heptanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, Dodecanoyl, tridecanoyl,
  • the ester group includes various hydrocarbyl ester groups or various substituted hydrocarbyl ester groups, and the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, amine substitution , Carboxyl substitution, hydroxy substitution or mercapto substitution, etc.
  • Specific examples include methyl ester group, ethyl ester group, n-propyl ester group, isopropyl ester group, n-butyl ester group, tert-butyl ester group, isobutyl ester group, pentyl ester group, 1-ethylpropyl ester group, 1-methylbutyl ester group, cyclopentyl ester group, hexyl ester group, 1-methylpentyl ester group, 1-ethylbutyl ester group, cyclohexyl ester group, 2-heptyl Ester group, heptyl group, octyl ester group, nonyl ester group, decyl ester group, undecyl ester group, dodecyl ester group, tridecyl ester group, tetradecyl ester group, pentadecyl ester group, ten Hexaalkyl ester group, heptade
  • the substituted amine group includes various hydrocarbyl substituted amine groups or various substituted hydrocarbyl substituted amine groups, and the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, Amino group substitution, carboxyl substitution, hydroxyl substitution or mercapto substitution, etc.
  • Specific examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, tert-butylamino, isobutylamino, pentylamino, 1 -Ethylpropylamino, 1-methylbutylamino, cyclopentylamino, hexylamino, 1-methylpentylamino, 1-ethylbutylamino, cyclohexylamino, 2-heptylamino , Heptylamino, octylamino, nonylamino, decylamino, undecylamino, dodecylamino, tridecylamino, tetradecylamino, pentadecylamino, hexadecane Amino, heptadecylamino, octadecylamino, nonade
  • the amide group includes various hydrocarbyl amide groups or various substituted hydrocarbyl amide groups, and the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, amide substitution , Carboxyl substitution, hydroxyl substitution or mercapto substitution, etc., for example, formamide, acetamide, n-propionamide, isopropionamide, n-butyramide, tert-butyramide, isobutyramide, valeramide, 1-ethylpropionamide, 1-methylbutyramide, cyclopentylamide, hexamide, 1-methylpentanamide, 1-ethylbutyramide, cyclohexylamide, 2-heptanoyl Amido, heptamido, octanamido, nonanoamido, decanamido, undecanoamido, dodecanoamido, tridecanoamid
  • the structure of the thiamine compound is represented by formula (1), R 1 and R 2 are hydrogen atoms, and R 3 is benzyl or 1,5 difluorophenyl.
  • the R 1 , R 2 , R 3 , R 4 or R 5 and R 6 independently represent a hydrogen atom or a C1-C18 chain hydrocarbon group, preferably the thiamine compound structure
  • R 1 or R 2 is independently a hydrogen atom or a C1-C4 chain hydrocarbon group
  • R 1 or R 2 is independently a hydrogen atom, methyl or ethyl
  • R 3 is C1- The C10 chain hydrocarbon group, considering the inhibitory effect on A ⁇ 40 and A ⁇ 42, further preferably, R 1 is a hydrogen atom
  • R 2 is a methyl group
  • R 3 is a methyl or ethyl group
  • R 1 is a methyl group
  • R 2 is a methyl group and R 3 is a vinyl group
  • the thiamine compound has the structure of formula (2)
  • R 4 and R 5 are hydrogen atoms
  • R 6 is n-propyl group.
  • the present invention also provides a method for preparing the above thiamine compound, which is obtained by reacting the thiamine phosphate represented by formula (1a) with the acid chloride represented by formula (1b) or (2b);
  • R 1 , R 2 , R 3 , R 4 or R 5 and R 6 are independently hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, ester group, carboxyl group, Hydroxyl, mercapto, hydrocarbon mercapto, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted hydrocarbyloxy, acyl or amide group.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned thiamine compounds and their isomers or salts of thiamine compounds and their isomers, preferably for the preparation of prevention and treatment
  • the drug for neurodegenerative diseases is further preferably a pharmaceutical composition for preparing a drug for preventing and treating Alzheimer's disease or aging.
  • the salt is a medically acceptable salt, such as lithium salt, sodium salt, potassium salt or calcium salt.
  • the composition can be made into tablets, powders, sprays, water injections, powder injections, rectal suppositories or skin patches (transdermal administration) according to a conventional method.
  • NMR shift ( ⁇ ) is given in ppm.
  • the measurement of NMR was performed using Bruker AVANCE-500 NMR instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), deuterated water (D 2 O), etc., internal standard It is tetramethylsilane (TMS).
  • MS Mass spectrometry
  • BCA protein concentration determination kit was purchased from Biyuntian, A ⁇ 40 and A ⁇ 42 detection kits were purchased from Wako Company, and cell culture related reagents were purchased from Gibico Company.
  • HEK293APP/sw overexpression cell culture cells are cultured in 48-well plates with DMEM culture medium (containing 10% FBS, 100 ⁇ g/mL G418 (Geneticin, geneticin) and double antibody) at 70% cell density Take 4mM stock solution of the test product (the test product is prepared by dissolving in DMEM culture solution), dilute to 400 ⁇ M with DMEM culture solution, add 500 ⁇ L per well, and culture for 24h.
  • DMEM culture medium containing 10% FBS, 100 ⁇ g/mL G418 (Geneticin, geneticin) and double antibody
  • the product 1-1 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-1 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-2 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-2 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-3 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-3 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • the product 1-4 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-4 was prepared for the biological test of the stock solution of the test product. The results are listed in Table 1.
  • the product 1-6 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-6 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-7 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-7 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-8 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-8 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • the product 1-9 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-9 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • the products 1-10 were subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The products 1-10 were prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-11 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-11 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • Example 4 Using the synthetic route of Example 4, the starting material 1-4b compound was replaced with 1-12b compound to obtain product 1-12.
  • the product 1-12 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-12 was prepared for the biological test of the stock solution of the test product. The results are listed in Table 1.
  • the ethyl acetate was extracted once.
  • the aqueous phase was adjusted to pH 3-4.
  • Dichloromethane was extracted. After extraction, the dichloromethane was added with anhydrous sodium sulfate to remove water. , Spin dry, dissolve the solid in methanol, add methyl tert-butyl ether, after stirring for five hours, a solid precipitates, and filter cake is dried at 45 °C to obtain product 1-13.
  • the product 1-13 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-13 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-14 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-14 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • the product 1-15 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-15 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-16 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-16 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-17 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-17 was prepared for the biological test of the stock solution of the test product. The results are listed in Table 1.
  • test sample stock solution was prepared with phenothiamine for biological testing, and the results are listed in Table 1.
  • the structured compounds compared with the blank of Comparative Example 1, the structured compounds all have A ⁇ 42 or/and A ⁇ 40 have an inhibitory effect; compared with Comparative Example 2 phenfosin, the content of A ⁇ 40 in Example 11 is comparable to that of Comparative Example 2.
  • the content is basically the same, but the content of A ⁇ 42 is reduced, indicating that it has a better inhibitory effect on A ⁇ 42; compared with Comparative Example 2 benfoti, Examples 5, 6 and 12, especially Example 12, A ⁇ 40 and A ⁇ 42 are both Significantly decreased, indicating that its inhibitory effect on A ⁇ 40 and A ⁇ 42 was greatly enhanced, indicating that its inhibitory effect on A ⁇ 40 and A ⁇ 42 was greatly enhanced.

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Abstract

Selon des modes de réalisation, la présente invention concerne une série de composés de thiamine ayant un groupe hydrocarboné ou un groupe hydrocarboné substitué fixé à (I), les composés ayant un effet inhibiteur sur Aβ40 et/ou Aβ42.
PCT/CN2019/120942 2018-11-28 2019-11-26 Composé de thiamine, son procédé de préparation et composition pharmaceutique associée WO2020108478A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2021531390A JP7307979B2 (ja) 2018-11-28 2019-11-26 チアミン化合物、製造方法及びその医薬組成物
US17/298,214 US11591354B2 (en) 2018-11-28 2019-11-26 Thiamine compound, preparation method and pharmaceutical composition thereof
EP19888995.8A EP3889160A4 (fr) 2018-11-28 2019-11-26 Composé de thiamine, son procédé de préparation et composition pharmaceutique associée
JP2023039009A JP2023085312A (ja) 2018-11-28 2023-03-13 チアミン化合物、製造方法及びその医薬組成物

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CN201811435584.X 2018-11-28
CN201811435584.XA CN111233925B (zh) 2018-11-28 2018-11-28 硫胺类化合物、制备方法及其药物组合物

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JP2024519938A (ja) * 2021-05-20 2024-05-21 シャンハイ、レイジング、ファーマシューティカル、カンパニー、リミテッド リン酸エステル基を含有する化合物、それを含有する医薬組成物、その調製方法、及びその使用
WO2023088457A1 (fr) * 2021-11-22 2023-05-25 上海日馨医药科技股份有限公司 Forme solide de dérivé de benfotiamine, son procédé de préparation et son utilisation

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EP3889160A1 (fr) 2021-10-06
CN111233925A (zh) 2020-06-05
US20220089621A1 (en) 2022-03-24
US11591354B2 (en) 2023-02-28
JP2022511468A (ja) 2022-01-31
JP2023085312A (ja) 2023-06-20
EP3889160A4 (fr) 2022-07-27
CN111233925B (zh) 2021-03-26
JP7307979B2 (ja) 2023-07-13

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